Viewpoint: Gentamicin for treatment of gonococcal urethritis in Malawi.

ViewPoint:Gentamicin for treatment of gonococcal urethritis in Malawi Gift Kamanga1, Chisale Mhango2, Lillian B. Brown3 1.University of North Carolina project, Kamuzu Central Hospital 2.Ministry of Health, Reproductive Health Unit 3..University of North Carolina at Chapel hill Gonococcal urethritis continues to be a public health problem in Malawi. Urethritis accounts for over 20% of outpatient STI clinic visits at Kamuzu Central Hospital in Lilongwe annually, and approximately 85% of urethritis is caused by Neisseria gonorrhoeae1-3. Timely and effective treatment of gonococcal urethritis eradicates infection in the affected individual, prevents the development of complications, and reduces the duration of infection, thus preventing onward transmission. Gonorrhea is also an important cofactor for HIV; Neisseria gonorrhoeae infection facilitates HIV transmission, while effective treatment of gonococcal urethritis reduces HIV shedding in the genital tract4. Additionally, acute HIV is important to HIV transmission5 and the Acute HIV Programme in Malawi found an association between urethritis and likelihood of acute HIV6. Therefore, attention to urethritis is of great public health importance for HIV prevention. Internationally, several antimicrobial surveillance projects exist to monitor the development and spread of resistance. Two major programs are the Gonococcal Antimicrobial Susceptibility Program (GASP) monitored by the World Health Organization, and the Gonococcal Isolate Surveillance Project (GISP) monitored by the US Centers for Disease Control and Prevention. These programs use laboratory methods to monitor in vitro gonococcal susceptibility and provide an objective measure of resistance. Clinical cure rates, which can be affected by reinfection, are used less often for resistance surveillance. Malawi adopted syndromic management of sexually transmitted infections in 1993. Based on clinical efficacy and cost, gentamicin 240mg IM and doxycycline 100 mg BID x 7 days was selected as the first line regimen to treat urethritis in the syndromic format7. Malawi continues to stand by its recommended use despite WHO and regional recommendations to use ciprofloxacin as first line treatment of uncomplicated gonococcal urethritis. Local surveillance data supports Malawi’s decision. A recent article in the journal Sexually Transmitted Diseases showed 100% susceptibility to gentamicin among men treated for urethritis in the outpatient sexually transmitted infections and reproductive health clinic at Kamuzu Central Hospital in Lilongwe1. In this article agar dilution minimum inhibitory concentration (MIC) testing conducted in the United States was used as the gold standard in parallel with less technologically challenging susceptibility methods of disc diffusion and e-test conducted here in Malawi. Results obtained from both MIC testing and the disc diffusion and E-tests performed locally were in agreement for the susceptible isolates. Trials conducted through a collaboration between the MOH and the University of North Carolina that determined clinical cure rates and/or laboratory based susceptibility data for men with gonoccocal urethritis in Malawi (in both Blantyre and Lilongwe) conducted in 1993, 1996, 1998, and 2001-2, and most recently in 2007, demonstrate continued susceptibility of gonorrhea to gentamicin at the >95% rate1,3,7. This continued high susceptibility to the first line drug regimen stands in contrast to other regions of the world and countries in southern Africa that implemented ciprofloxacin as first line treatment. South Africa saw the proportion of gonococcal isolates resistant to ciprofloxacin increase from zero to over 40% within 18 months after it was introduced as first line treatment for gonococcal urethritis8,9. This dramatic reduction in susceptibility necessitated a switch to more costly drugs, such as cephalosporins. Although the 2007 GC susceptibility survey shows ciprofloxacin to continue to be susceptible in Malawi, it can be expected that resistance would rapidly develop if its use to treat urethritis were increased. Cost-effective control of gonococcal urethritis is essential in Malawi, particularly given its synergy with HIV. We believe that the Malawi Ministry of Health made the right choice to continue to recommend gentamicin for first line treatment. Toxicity related to gentamicin is related to cumulative doses, and there are no reported toxicities to a single intramuscular injection. However, this has not been looked at systematically and more data are needed on the safety profile of and proper dosing of gentamicin for treatment of gonococcal urethritis. Additionally, as antimicrobial susceptibilities of prevailing gonococcal strains can change rapidly due to the nature of the bacteria, accurate and periodic assessments of susceptibility patterns are needed. Sustaining an accredited microbiology laboratory is challenging, hence previously the majority of the gonococcal susceptibility testing has been performed in external labs outside of Malawi. It’s encouraging to note that the e-test and disc diffusion testing were successfully conducted in Malawi and further refinement of these techniques will reduce the dependency on costly testing abroad. While the gold standard for gonococcal microbial sensitivity monitoring is Minimum Inhibitory Concentration (MIC), our study demonstrated high level of agreement between less technically demanding and less expensive tests such as disk diffusion and E-test with the gold standard for susceptible isolates. The use of a turbidometer to standardize turbidity of the culture suspension on the media likely improved the correlation between methods compared to previous susceptibility surveys2. This is important because it shows feasibility of microbial susceptibility monitoring in limited resource setting like Malawi. Continued surveillance is necessary to ensure treatment guidelines are in line with current susceptibility trends. Sustaining the local laboratory support will be crucial to these efforts.